Star Polymer-Drug Conjugates with pH-Controlled Drug Release and Carrier Degradation

In this study, we describe the design, synthesis, and physicochemical and preliminary biological characteristics of new biodegradable, high-molecular-weight (HMW) drug delivery systems with star-like architectures bearing the cytotoxic drug doxorubicin (DOX) attached by a hydrazone bond-containing spacer. The star polymers were synthesized by grafting semitelechelic N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers on a 2,2-bis(hydroxymethyl)propionic acid- (bis-MPA-) based polyester dendritic core. The molecular weight of the star polymers ranged from 280 to 450 000 g/mol and could be adjusted by proper selection of the bis-MPA dendrimer generation and by considering the polymer to dendrimer molar ratio. The biodegradation of the polymer conjugates is based on the spontaneous slow hydrolysis of the dendritic core in neutral physiological conditions. Hydrazone spacers in the conjugates were fairly stable at neutral pH (7.4) mimicking blood stream conditions, and DOX was released from the conjugates under mild acidic conditions simulating the tumor cell microenvironment in endosomes and lysosomes (pH 5). Finally, we have shown the significant in vitro cytotoxicity of the star polymer-DOX conjugate on selected cancer cell lines with IC50 values almost comparable with that of the free drug and higher than that observed for a linear polymer-DOX conjugate with much lower molecular weight.

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Low-Molecular-Weight Polyethyleneimine Grafted Polythiophene for Efficient siRNA Delivery

BioMed Research International ◽

10.1155/2015/406389 ◽

2015 ◽

Vol 2015 ◽

pp. 1-9 ◽

Cited By ~ 4

Author(s):

Pan He ◽

Kyoji Hagiwara ◽

Hui Chong ◽

Hsiao-hua Yu ◽

Yoshihiro Ito

Keyword(s):

Molecular Weight ◽

Sirna Delivery ◽

Fluorescent Microscopy ◽

Molar Ratio ◽

Low Molecular Weight ◽

Label Free ◽

Endosomal Membrane ◽

Cationic Copolymers ◽

Interfering Rna

Owing to its hydrophilicity, negative charge, small size, and labile degradation by endogenous nucleases, small interfering RNA (siRNA) delivery must be achieved by a carrier system. In this study, cationic copolymers composed of low-molecular-weight polyethylenimine and polythiophenes were synthesized and evaluated as novel self-tracking siRNA delivery vectors. The concept underlying the design of these copolymers is that hydrophobicity and rigidity of polythiophenes should enhance the transport of siRNA across the cell membrane and endosomal membrane. A gel retardation assay showed that the nanosized complexes formed between the copolymers and siRNA were stable even at a molar ratio of 1 : 2. The high cellular uptake (>80%) and localization of the copolymer vectors inside the cells were easily analyzed by tracking the fluorescence of polythiophene using fluorescent microscopy and cytometry. Anin vitroluciferase knockdown (KD) assay in A549-luc cells demonstrated that the siRNA complexes with more hydrophobic copolymers achieved a higher KD efficiency of 52.8% without notable cytotoxicity, indicating protein-specific KD activity rather than solely the cytotoxicity of the materials. Our polythiophene copolymers should serve as novel, efficient, low cell toxicity, and label-free siRNA delivery systems.

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Design, synthesis and in vitro cytotoxicity of novel dinuclear platinum(II) complexes

Bioorganic & Medicinal Chemistry Letters ◽

10.1016/j.bmcl.2011.01.064 ◽

2011 ◽

Vol 21 (6) ◽

pp. 1763-1766 ◽

Cited By ~ 15

Author(s):

Chuanzhu Gao ◽

Shaohua Gou ◽

Lei Fang ◽

Jian Zhao

Keyword(s):

In Vitro Cytotoxicity ◽

Design Synthesis ◽

Dinuclear Platinum

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Betulinic Acid-Nitrogen Heterocyclic Derivatives: Design, Synthesis, and Antitumor Evaluation in Vitro

Molecules ◽

10.3390/molecules25040948 ◽

2020 ◽

Vol 25 (4) ◽

pp. 948

Author(s):

Yuqin Yang ◽

Tianxin Xie ◽

Xuehao Tian ◽

Nana Han ◽

Xiaojing Liu ◽

...

Keyword(s):

Betulinic Acid ◽

Antitumor Agents ◽

In Vitro Cytotoxicity ◽

Design Synthesis ◽

Pentacyclic Triterpenoid ◽

Heterocyclic Derivatives ◽

Staining Techniques ◽

Antitumor Evaluation ◽

Nitrogen Heterocyclic

Betulinic acid (BA) is a star member of the pentacyclic triterpenoid family, which exhibits great prospects for antitumor drug development. In an attempt to develop novel antitumor candidates, 21 BA-nitrogen heterocyclic derivatives were synthetized, in addition to four intermediates, 23 of which were first reported. Moreover, they were screened for in-vitro cytotoxicity against four tumor cell lines (Hela, HepG-2, BGC-823 and SK-SY5Y) by a standard methylthiazol tetrazolium (MTT) assay. The majority of these derivatives showed much stronger cytotoxic activity than BA. Remarkably, the most potent compound 7e (the half maximal inhibitory concentration (IC50) of which was 2.05 ± 0.66 μM) was 12-fold more toxic in vitro than BA-treated Hela. Furthermore, multiple fluorescent staining techniques and flow cytometry collectively revealed that compound 7e could induce the early apoptosis of Hela cells. Structure–activity relationships were also briefly discussed. The present study highlighted the importance of introducing nitrogen heterocyclic rings into betulinic acid in the discovery and development of novel antitumor agents.

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Design, Synthesis and in vitro Cytotoxicity Studies of Novel Pyrrolo[2,1][1,4]benzodiazepine-glycosylated Pyrrole and Imidazole Polyamide Conjugates.

ChemInform ◽

10.1002/chin.200404224 ◽

2004 ◽

Vol 35 (4) ◽

Author(s):

Rohtash Kumar ◽

J. William Lown

Keyword(s):

In Vitro Cytotoxicity ◽

Design Synthesis ◽

Cytotoxicity Studies

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Rapid in situ cross-linking of hydrogel adhesives based on thiol-grafted bio-inspired catechol-conjugated chitosan

Journal of Biomaterials Applications ◽

10.1177/0885328217738403 ◽

2017 ◽

Vol 32 (5) ◽

pp. 612-621 ◽

Cited By ~ 6

Author(s):

Zhiwen Zeng ◽

Xiumei Mo

Keyword(s):

Soft Tissues ◽

Sodium Periodate ◽

Oxidation Mechanism ◽

Thiol Group ◽

In Vitro Cytotoxicity ◽

Tissue Adhesive ◽

Molar Ratio ◽

Adhesive Properties

In this paper, a novel chitosan derivative, thiol-grafting bio-inspired catechol-conjugated chitosan was synthesized. The chemical structure of the synthesized catechol-conjugated chitosan was verified by 1H NMR, and its contents of thiol group and catechol group were determined by UV-vis spectrum. Four percent of catechol-conjugated chitosan aqueous solution could form hydrogels rapidly in situ in 1 min or less with the addition of sodium periodate. Rheological studies showed that the mechanical properties depend on the concentrations of catechol-conjugated chitosan and the molar ratio of sodium periodate to catechol groups. Additionally, the adhesive properties of the resulting adhesives were evaluated, and the adhesion strength of obtained adhesives was as high as 50 kPa because of the complex and multiple interactions, especially the anti-oxidation mechanism of thiol group. The in vitro cytotoxicity assays demonstrated an excellent biocompatibility of the catechol-conjugated chitosan hydrogels. Benefiting from the in situ fast cured, desired mechanical strength, biocompatibility and relatively high adhesion performance, these properties suggested that catechol-conjugated chitosan hydrogel adhesives have potential applications as tissue adhesive for soft tissues.

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In vitro synergistic potentials of novel antibacterial combination therapies against Salmonella Typhimurium and Escherichia coli

10.21203/rs.2.9511/v3 ◽

2019 ◽

Author(s):

Md. Akil Hossain ◽

Hae-Chul Park ◽

Kwang-jick Lee ◽

Sung-Won Park ◽

Seung-Chun Park ◽

...

Keyword(s):

Escherichia Coli ◽

Synergistic Effects ◽

Clinical Importance ◽

Blood Stream ◽

In Vitro Cytotoxicity ◽

Farm Animals ◽

Epicatechin Gallate ◽

E Coli

Abstract Background: The antibiotics generally used in farm animals are rapidly losing their effectiveness all over the world as bacteria develop antibiotic resistance. New strategies are needed to block the development of resistance and to prolong the life of traditional antibiotics. This study aimed to increase the efficacy of existing antibiotics by combining them with the opportunistic phenolic compounds gallic acid (GA), epicatechin, epicatechin gallate, epigallocatechin and hamamelitannin. Fractional inhibitory concentration index (FICI) of phenolic compound-antibiotic combinations against Salmonella enterica serovar Typhimurium (S. Typhimurium) and Escherichia coli (E. coli) were determined. Based on the FICI and clinical importance, 3 combinations were selected to evaluate their effects on the virulence factors of these bacteria. The in vitro cytotoxicity of GA and hamamelitannin in Rattus norvegicus (IEC-6) cell lines were evaluated. Results: Minimum inhibitory concentrations (MICs) of epigallocatechin, GA and hamamelitannin found against different strains were (512–1024), (256–1024) and (512–2048) μg/mL, respectively. Synergistic effects were obtained from combinations of thiamphenicol-GA (FICI: 0.28), erythromycin-hamamelitannin (FICI: 0.38) and thiamphenicol-hamamelitannin (FICI: 0.50) against E. coli, and erythromycin-epicatechin gallate (FICI: 0.50) against S. Typhimurium. Moreover, additive effects were obtained from 33 combinations against S. Typhimurium (FICI: 0.502~0.750) and E. coli (FICI: 0.502~0.625). The time-kill assays and ultrastructural morphology showed that GA-ceftiofur, and hamamelitannin-erythromycin and GA-ampicillin combinations more efficiently inhibited the growth of S. Typhimurium and E. coli, respectively, compared to individual antibiotics. Biofilm viability and swimming and swarming motilities of S. Typhimurium in presence of GA-ceftiofur, and E. coli in presence of hamamelitannin-erythromycin and GA-ampicillin combinations were more competently inhibited than individual antimicrobials. The inhibitory concentrations 50% (IC50) of GA and hamamelitannin in IEC-6 cells were 564.55 μM and 988.54 μM, respectively. Conclusions: This study suggest that GA-ceftiofur combination can be potential medication to treat S. Typhimurium-associated diarrhea and prevent S. Typhimurium-associated blood-stream infections (e.g.: fever) in farm animals. Hamamelitannin-erythromycin and GA-ampicillin combinations can be effective in restricting E. coli contamination in farm animals, and ultimately its transmission from animal to human. Further study to confirm these effects and safety profiles in in vivo system should be undertaken for establishing these combinations as medications.

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Physicochemical and Biological Examination of Two Glatiramer Acetate Products

Biomedicines ◽

10.3390/biomedicines7030049 ◽

2019 ◽

Vol 7 (3) ◽

pp. 49 ◽

Cited By ~ 1

Author(s):

Komlosh ◽

Weinstein ◽

Loupe ◽

Hasson ◽

Timan ◽

...

Keyword(s):

Molecular Weight ◽

High Molecular Weight ◽

Glatiramer Acetate ◽

Active Ingredient ◽

In Vitro Cytotoxicity ◽

Exchange Chromatography ◽

Size Exclusion ◽

Potency Assay ◽

Scientific Discussion

Herein we compared 40 mg/mL lots of the active ingredient, glatiramer acetate, manufactured by Mylan/Natco to the active ingredient, glatiramer acetate in Copaxone (Teva Pharmaceuticals, Ltd., Netanya Israel) using physicochemical (PCC) methods and biological assays. No differences were seen between the Mylan/Natco and Teva lots with some low resolution release PCC assays (amino acid analysis, molecular weight distribution, interaction with Coomassie Brilliant Blue G-250). Changes in polydispersity between Mylan/Natco and Copaxone lots were found using size exclusion chromatography and the high resolution PCC method, known as Viscotek, and suggestive of a disparity in the homogeneity of mixture, with a shift towards high molecular weight polypeptides. Using RPLC-2D MALLS, 5 out of 8 Mylan/Natco lots fell outside the Copaxone range, containing a high molecular weight and high hydrophobicity subpopulation of polypeptides not found in Copaxone lots. Cation exchange chromatography showed differences in the surface charge distribution between the Copaxone and Mylan/Natco lots. The Mylan/Natco lots were found to be within Copaxone specifications for the EAE model, monoclonal and polyclonal binding assays and the in vitro cytotoxicity assay, however higher IL-2 secretion was shown for three Mylan/Natco lots in a potency assay. These observations provide data to inform the ongoing scientific discussion about the comparability of glatiramer acetate in Copaxone and follow-on products.

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Design, Synthesis and In Vitro Characterization of Novel Antimicrobial Agents Based on 6-Chloro-9H-carbazol Derivatives and 1,3,4-Oxadiazole Scaffolds

Molecules ◽

10.3390/molecules25020266 ◽

2020 ◽

Vol 25 (2) ◽

pp. 266 ◽

Cited By ~ 5

Author(s):

Alexandra T. Bordei Telehoiu ◽

Diana C. Nuță ◽

Miron T. Căproiu ◽

Florea Dumitrascu ◽

Irina Zarafu ◽

...

Keyword(s):

Antimicrobial Activity ◽

Antimicrobial Agents ◽

Oral Absorption ◽

Phosphorus Oxychloride ◽

In Vitro Cytotoxicity ◽

Mutagenic Potential ◽

Design Synthesis ◽

Acyl Chlorides ◽

Hydrazide Derivative

In this paper, we aimed to exploit and combine in the same molecule the carbazole and the 1,3,4-oxadiazole pharmacophores, to obtain novel carprofen derivatives, by using two synthesis pathways. For the first route, the following steps have been followed: (i) (RS)-2-(6-chloro-9H-carbazol-2-yl)propanonic acid (carprofen) treatment with methanol, yielding methyl (RS)-2-(6-chloro-9H-carbazol-2-yl)propanoate; (ii) the resulted methylic ester was converted to (RS)-2-(6-chloro-9H-carbazol-2-yl)propane hydrazide (carprofen hydrazide) by treatment with hydrazine hydrate; (iii) reaction of the hydrazide derivative with acyl chlorides led to N-[(2RS)-2-(6-chloro-9H-carbazol-2-yl)propanoil]-N′-R-substituted-benzoylhydrazine formation, which; (iv) in reaction with phosphorus oxychloride gave the (RS)-1-(6-chloro-9H-carbazol-2-yl)-1-(1,3,4-oxadiazol-2-yl)ethane derivatives. In the second synthesis pathway, new 1,3,4-oxadiazole ring compounds were obtained starting from carprofen which was reacted with isoniazid, in the presence of phosphorus oxychloride to form (RS)-1-(6-chloro-9H-carbazol-2-yl)-1-[5-(4-pyridyl)-1,3,4-oxadiazol-2-yl]ethane. The synthesized compounds were characterized by IR, 1H-NMR and 13C-NMR, screened for their drug-like properties and evaluated for in vitro cytotoxicity and antimicrobial activity. The obtained compounds exhibited a good antimicrobial activity, some of the compounds being particularly active on E. coli, while others on C. albicans. The most significant result is represented by their exceptional anti-biofilm activity, particularly against the P. aeruginosa biofilm. The cytotoxicity assay revealed that at concentrations lower than 100 μg/mL, the tested compounds do not induce cytotoxicity and do not alter the mammalian cell cycle. The new synthesized compounds show good drug-like properties. The ADME-Tox profiles indicate a good oral absorption and average permeability through the blood brain barrier. However, further research is needed to reduce the predicted mutagenic potential and the hepatotoxicity.

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